2-methoxyethyl methanesulfonate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-ol (2.9 g, 0.01 mol), 2-methoxyethyl methane sulfonate (4.6 g, 0.03 mol, 3 equiv), and cesium carbonate (9.9 g, 0.03 mol, 3 equiv) in DMF (100 ml) was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into cold water, the solid was filtrated and dried to give 1.5 g product. MS (ESI) m/z: 350 (M+1). the solid was filtrated dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methanesulfonic acid 2-methoxyethyl ester (70.5 mg, 0.50 mmol) and 2-[2-chloro-5-hydroxyphenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (Preparation 66,100 mg, 0.42 mmol) were stirred together in N,N-dimethylacetamide (4 ml). Potassium carbonate (58 mg, 0.42 mmol) was added and the resultant solution was heated to 100° C. for 10 hours. The reaction mixture was cooled then quenched with water (10 ml) and extracted with ethylacetate (10 ml). The organic layer was dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to give crude title compound. Material taken on without further purification. The reaction mixture was cooled then quenched with water (10 ml) extracted with ethylacetate (10 ml) The organic layer was dried over anhydrous MgSO4 (s) filtered evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 17 g of N-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide and 6 g of 2-methoxyethyl mesylate and 6.9 g of K2CO3 was refluxed in acetonitril for 20 h. The resulting mixture was filtered and evaporated. The residue was dissolved in methylene chloride and extracted with water containing 1 g of NaOH, then with water and then dried over Na2SO4, filtered and evaporated. The residue was crystallized from ethyl acetate yielding N-(2-((2-hydroxy-3-(4-(2-methoxyethoxy)phenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide. Melting point 69° C. (base). The resulting mixture was filtered evaporated The residue was dissolved in methylene chloride extracted with water containing 1 g of NaOH with water and then dried over Na2SO4 filtered evaporated The residue was crystallized from ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromofluorene (2.45 g, 10 mmol) in tetrahydrofuran (dry, 75 ml) was added potassium t-butoxide (3.36 g, 30 mmol), giving a deep orange solution. The mixture was stirred at ambient temperature for 10 min and added 2-methoxyethyl mesylate in tetrahydrofuran dropwise. Exothermic reaction was observed. Stirring was continued at ambient temperature for overnight to give an orange solution. At the end of the reaction, it was diluted with water (150 ml). The products extracted with ethylacetate (30 ml) and washed with water. Organic layer was dried over magnesium sulfate and concentrated in vacuuo to afford the crude product. It was purified by preparative thin layer chromatography (silica gel, Rf=0.3 using hexane-EtOAc/3:2 as eluent) to give 2-bromo-9,9-dimethoxyethylfluorene (3.3 g). giving a deep orange solution Exothermic reaction Stirring was continued at ambient temperature for overnight to give an orange solution At the end of the reaction, it The products extracted with ethylacetate (30 ml) washed with water Organic layer was dried over magnesium sulfate concentrated in vacuuo to afford the crude product It was purified by preparative thin layer chromatography (silica gel, Rf=0.3 using hexane-EtOAc/3:2 as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromofluorene (2.45 g, 10 mmol) in tetrahydrofuran (dry, 75 ml) was added potassium t-butoxide (3.36 g, 30 mmol), giving a deep orange solution. The mixture was stirred at ambient temperature for 10 min and added 2-methoxyethyl mesylate in tetrahydrofuran dropwise. Exothermic reaction was observed. Stirring was continued at ambient temperature for overnight to give an orange solution. At the end of the reaction, it was diluted with water (150 ml). The products extracted with ethylacetate (30 ml) and washed with water. Organic layer was dried over magnesium sulfate and concentrated in vacuuo to afford the crude product. It was purified by preparative thin layer chromatography (silica gel, Rf=0.3 using hexane-EtOAc/3:2 as eluent) to give 2-bromo-9,9-dimethoxyethylfluorene (3.3 g). giving a deep orange solution Exothermic reaction Stirring was continued at ambient temperature for overnight to give an orange solution At the end of the reaction, it The products extracted with ethylacetate (30 ml) washed with water Organic layer was dried over magnesium sulfate concentrated in vacuuo to afford the crude product It was purified by preparative thin layer chromatography (silica gel, Rf=0.3 using hexane-EtOAc/3:2 as eluent)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-[2-fluoro-4-(1H-tetrazol-1-yl)-phenyl]-2-(piperidin-4-yl)-benzo[d]oxazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DMF (2 ml) and added K2CO3 (40 mg, 0.29 mmol) and stirred the mixture at rt for 15 mins. To this mixture added 2-methoxyethyl methanesulfonate (45 mg, 0.29 mmol) and stirred at rt for 17 h. Work up (EtOAc/H2O) followed by purification by column chromatography on 60-120 mesh silicagel using a gradient mixture of DCM and MeOH (98:2) as eluent afforded the titled compound (90 mg) as a brown solid (15 mg). M.P.: 148-152° C. MS (m/z): 423.3 [M+H]+. stirred at rt for 17 h followed by purification by column chromatography on 60-120 mesh silicagel a gradient mixture of DCM and MeOH (98:2) as eluent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-ol (2.9 g, 0.01 mol), 2-methoxyethyl methane sulfonate (4.6 g, 0.03 mol, 3 equiv), and cesium carbonate (9.9 g, 0.03 mol, 3 equiv) in DMF (100 ml) was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into cold water, the solid was filtrated and dried to give 1.5 g product. MS (ESI) m/z: 350 (M+1). the solid was filtrated dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-ol (2.9 g, 0.01 mol), 2-methoxyethyl methane sulfonate (4.6 g, 0.03 mol, 3 equiv), and cesium carbonate (9.9 g, 0.03 mol, 3 equiv) in DMF (100 ml) was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into cold water, the solid was filtrated and dried to give 1.5 g product. MS (ESI) m/z: 350 (M+1). the solid was filtrated dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 2-methoxyethanol (Aldrich, 94 mg, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 2-methoxyethanol (Aldrich, 94 mg, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.22 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.7 g of 60% NaH are added and stirred for 30 mins. 0.24 g of 2-methoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured into a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.1 g (yield=39%) of 9-(2-methoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics: the mixture is heated with reflux for 3 h After returning to RT The organic phase is decanted washed with a solution saturated with NaCl dried with magnesium sulfate The solvents are evaporated The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.22 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.7 g of 60% NaH are added and stirred for 30 mins. 0.24 g of 2-methoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured into a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.1 g (yield=39%) of 9-(2-methoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics: the mixture is heated with reflux for 3 h After returning to RT The organic phase is decanted washed with a solution saturated with NaCl dried with magnesium sulfate The solvents are evaporated The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5)